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In addition to essential roles in protein synthesis, lysyl-tRNA synthetase (KRS) is secreted to trigger a proinflammatory function that induces macrophage activation and TNF-α secretion. KRS has been associated with autoimmune diseases such as polymyositis and dermatomyositis. In this study, we investigated the immunomodulatory effects of KRS on bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and subsequent polarization of Th cells and analyzed the underlying mechanisms. KRS-treated DCs increased the expression of cell surface molecules and proinflammatory cytokines associated with DC maturation and activation. Especially, KRS treatment significantly increased production of IL-12, a Th1-polarizing cytokine, in DCs. KRS triggered the nuclear translocation of the NF-κB p65 subunit along with the degradation of IκB proteins and the phosphorylation of MAPKs in DCs. Additionally, JNK, p38, and ERK inhibitors markedly recovered the degradation of IκB proteins, suggesting the involvement of MAPKs as the upstream regulators of NF-κB in the KRS-induced DC maturation and activation. Importantly, KRS-treated DCs strongly increased the differentiation of Th1 cells when cocultured with CD4 + T cells. The addition of anti-IL-12-neutralizing Ab abolished the secretion of IFN-γ in the coculture, indicating that KRS induces Th1 cell response via DC-derived IL-12. Moreover, KRS enhanced the OVA-specific Th1 cell polarization in vivo following the adoptive transfer of OVA-pulsed DCs. Taken together, these results indicated that KRS effectively induced the maturation and activation of DCs through MAPKs/NF-κB-signaling pathways and favored DC-mediated Th1 cell response., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Myeloid-derived suppressor cells (MDSCs) contribute to tumor-mediated immune escape by suppressing antitumor immune responses. Interleukin-33 (IL-33) is capable of regulating various immune cell populations; however, the effects of IL-33 on the differentiation of MDSCs have not been well characterized. In this study, we evaluated the effects of IL-33 on MDSCs and found that IL-33 significantly reduced the differentiation of lineage-negative bone marrow progenitor cells into granulocytic MDSCs (G-MDSCs). IL-33-treated MDSCs exhibited diminished immunosuppressive capacity; reduced inhibition on T-cell proliferation and interferon-γ production, and diminished production of reactive oxygen species. However, IL-33 treatment did not affect the frequency of monocytic MDSCs (M-MDSCs) or their production of nitric oxide and expression of arginase-1. Additionally, compared with control MDSCs, IL-33-treated MDSCs had reduced capacity to induce the differentiation or expansion of Treg cells. Moreover, in vivo IL-33 administration significantly decreased MDSCs and G-MDSCs accumulation in the spleen and tumor microenvironment. Also, despite increasing CD4 + and CD8 + T-cell infiltration, IL-33 administration markedly decreased Treg-cell population in tumor microenvironment. Taken together, our findings indicate that IL-33 reduces the frequency and immunosuppressive activity of G-MDSCs and ultimately the extent of tumor growth.

Ceramides, sphingosine-based lipid molecules, are generated mainly from the hydrolysis of sphingomyelin and play pivotal roles in biological processes including cell growth, differentiation, and inflammation. In this study, we investigated the effect of exogenous ceramides on the differentiation of regulatory T (Treg) cells and expression of FoxP3 gene in Treg cells. A cell-permeable C6-ceramide (C6) was capable of upregulating Treg cell differentiation when acting together with transforming growth factor-beta (TGF-β), and this induction was independent of T-cell receptor (TCR) and CD28 strength. Additionally, TGF-β/C6 treatment sustained the expression of FoxP3 gene in Treg cells, as the percentages of FoxP3(+) Treg cells in the TGF-β/C6-treated group remained high for prolonged periods compared to those in the group treated with TGF-β alone. Furthermore, C8-ceramide was also capable of sustaining Treg cell populations and FoxP3 expression, whereas C2-, C16-, and C24-ceramides did not. Importantly, adoptive transfer of the TGF-β/C6-induced Treg cells into syngenic mice showed that TGF-β/C6-induced Treg cells maintained their FoxP3 expression in vivo significantly longer periods than the TGF-β-induced Treg cells. Taken together, our findings indicate that C6 can be utilized to increase Treg cell populations and also to sustain their FoxP3 expression in the treatment of autoimmune diseases or graft rejection., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

IL-32, a newly described multifunctional cytokine, has been associated with a variety of inflammatory diseases, including rheumatoid arthritis, vasculitis, and Crohn's disease. In this study, we investigated the immunomodulatory effects of IL-32γ on bone marrow-derived dendritic cell (DC)-driven Th responses and analyzed the underlying signaling events. IL-32γ-treated DCs exhibited upregulated expression of cell-surface molecules and proinflammatory cytokines associated with DC maturation and activation. In particular, IL-32γ treatment significantly increased production of IL-12 and IL-6 in DCs, which are known as Th1- and Th17-polarizing cytokines, respectively. This increased production was inhibited by the addition of specific inhibitors of the activities of phospholipase C (PLC), JNK, and NF-κB. IL-32γ treatment increased the phosphorylation of JNK and the degradation of both IκBα and IκBβ in DCs, as well as NF-κB binding activity to the κB site. The PLC inhibitor suppressed NF-κB DNA binding activity and JNK phosphorylation increased by IL-32γ treatment, thereby indicating that IL-32γ induced IL-12 and IL-6 production in DCs via a PLC/JNK/NF-κB signaling pathway. Importantly, IL-32γ-stimulated DCs significantly induced both Th1 and Th17 responses when cocultured with CD4(+) T cells. The addition of a neutralizing anti-IL-12 mAb abolished the secretion of IFN-γ in a dose-dependent manner; additionally, the blockage of IL-1β and IL-6, but not of IL-21 or IL-23p19, profoundly inhibited IL-32γ-induced IL-17 production. These results demonstrated that IL-32γ could effectively induce the maturation and activation of immature DCs, leading to enhanced Th1 and Th17 responses as the result of increased IL-12 and IL-6 production in DCs.

AIMP1 (ARS-interacting multifunctional protein 1), previously known as p43, was initially identified as a factor associated with a macromolecular tRNA synthetase complex. Recently, we demonstrated that AIMP1 is also secreted and acts as a novel pleiotropic cytokine. In this study, we investigated whether AIMP1 induces the activation and maturation of murine bone marrow-derived dendritic cells (DCs). AIMP1-treated DCs exhibited up-regulated expression of cell-surface molecules, including CD40, CD86, and MHC class II. Additionally, microarray analysis and RT-PCR determinations indicated that the expression of known DC maturation genes also increased significantly following treatment with AIMP1. Treatment of DCs with AIMP1 resulted in a significant increase in IL-12 production and Ag-presenting capability, and it also stimulated the proliferation of allogeneic T cells. Importantly, AIMP1-treated DCs induced activation of Ag-specific Th type 1 (Th1) cells in vitro and in vivo. AIMP1-stimulated DCs significantly enhanced the IFN-gamma production of cocultured CD4+ T cells. Immunization of mice with keyhole limpet hemocyanin-pulsed AIMP1 DCs efficiently led to Ag-specific Th1 cell responses, as determined by flow cytometry and ELISA. The addition of a neutralizing anti-IL-12 mAb to the cell cultures that had been treated with AIMP1 resulted in the decreased production of IFN-gamma, thereby indicating that AIMP1-stimulated DCs may enhance the Th1 response through increased production of IL-12 by APCs. Taken together, these results indicate that AIMP1 protein induces the maturation and activation of DCs, which skew the immune response toward a Th1 response.

Induction of differentiation is a new and promising approach to cancer therapy, well illustrated by the treatment of acute myeloid leukemia with all-trans retinoic acid (ATRA). Using combination of ATRA and chemotherapy, adverse effects such as retinoic acid syndrome have decreased, and long-term survival has improved. In this study, we demonstrated that the indeno[1,2-c]isoquinolines markedly enhanced differentiation of human myeloid leukemia HL-60 and NB4 cells when simultaneously combined with a low dose of ATRA. Of the tested compounds, 6-(4-methoxybenzyl)-2,11-dimethyl-6H,11H-indeno[1,2-c]isoquinolin-5-one (IIQ-16), an indeno[1,2-c]isoquinoline derivative, showed the highest differentiation-enhancing activity via a pathway involved with protein kinase C, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. The ability to enhance the differentiation potential of ATRA by IIQ-16 may improve outcomes in the therapy of acute promyelocytic leukemia.

The erythroid differentiation regulator 1 (Erdr1), which is a novel and highly conserved factor, was recently reported to be negatively regulated by IL-18 and to play a crucial role as an antimetastatic factor. IL-18 is a proinflammatory cytokine that functions as an angiogenic mediator in inflammation. Rosacea is a chronic inflammatory skin disorder that is characterized by abnormal inflammation and vascular hyperactivity of the facial skin. To determine whether Erdr1 contributes to the regulation of the chronic inflammatory process in the development of rosacea, an immunohistochemical analysis was performed in healthy donors and patients with rosacea. In this study, we showed that Erdr1 was downregulated, whereas IL-18 was upregulated, in patients with rosacea, which led us to question the role of Erdr1 in this disorder. Moreover, a rosacea-like BALB/c mouse model was used to determine the role of Erdr1 in rosacea in vivo. LL-37 injection induced typical rosacea features, including erythema, telangiectasia and inflammation. Treatment with recombinant Erdr1 (r Erdr1) resulted in a significant reduction of erythema, inflammatory cell infiltration (including CD4+ and CD8+ T cells), and microvessel density with vascular endothelial growth factor ( VEGF). Taken together, our findings suggest that r Erdr1 may be involved in attenuating the inflammation and angiogenesis associated with the pathogenesis of rosacea. Thus, these results provide new insight into the mechanism involved in this condition and indicate that r Erdr1 could be a potential target for therapeutic intervention of rosacea. [ABSTRACT FROM AUTHOR]

Erythroid differentiation regulator 1 (Erdr1) has been identified as an anti-inflammatory factor in several disease models, including collagen-induced arthritis (CIA), but its exact mechanisms are still not fully understood. Here, the involvement of regulatory T (Treg) cells in Erdr1-improved CIA was investigated. In the CIA model, Erdr1 was confirmed to reduce collagen-specific IgM in plasma and plasma cells in draining lymph nodes. Importantly, the downregulated Treg cell ratio in draining lymph nodes from CIA mice was recovered by Erdr1 treatment. In addition, administration of Erdr1 improved the CIA score and joint tissue damage, while it revealed no effect in Treg cell-depleted CIA mice, indicating that Treg cells mediate the therapeutic effects of Erdr1 in the CIA model. Results from in vitro experiments also demonstrated that Erdr1 significantly induced Treg cell differentiation and the expression of Treg activation markers, including CD25, CD69, and CTLA4 in CD4+Foxp3+ cells. Furthermore, Erdr1-activated Treg cells dramatically suppressed the proliferation of responder T cells, suggesting that they are functionally active. Taken together, these results show that Erdr1 induces activation of Treg cells and ameliorates rheumatoid arthritis via Treg cells. [ABSTRACT FROM AUTHOR]

In addition to a role in translation, AIMP1 is secreted to affect various immune cells, such as macrophages, dendritic cells, B cells, and natural killer cells. However, the direct effects of AIMP1 on T cells have not yet been reported. In this study, we investigated whether AIMP1 could modulate T cell responses directly. Results revealed that AIMP1 significantly inhibited T cell receptor (TCR)-dependent activation and proliferation of CD4 T cells, as well as decreased TCR stimuli-induced Ca2+ influx in CD4 T cells. In addition, microscopic analysis revealed that lipid raft association in response to TCR engagement was significantly reduced in the presence of AIMP1, and the phosphorylation of PLCγ and PI3K was also down-regulated in CD4 T cells by AIMP1. Furthermore, AIMP1 specifically enhanced the differentiation of regulatory T (Treg) cells, while it had no effect on T helper type 1 (Th1), type 2 (Th2), and type 17 (Th17) cell differentiation. Collectively, these results indicate that AIMP1 affects T cells directly by down-regulating TCR signaling complex formation and inducing Treg cell differentiation in CD4 T cells. • Aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1) inhibits TCR mediated activation and proliferation of CD4 T cells. • AIMP1 regulates Ca2+ influx and lipid raft aggregation in TCR-stimulated CD4 T cells. • The inhibitory function of AIMP1 on TCR signaling specifically enhances Treg cell differentiation. [ABSTRACT FROM AUTHOR]

Highlights: [•] Dendritic cells (DCs) of mice lacking IL-12p40 and/or IL-18 were compared. [•] Deficiency of IL-12p40 and/or IL-18 in DCs showed similar surface phenotypes. [•] IL-12p40/IL-18-deficient DCs showed decreased IL-10 production. [•] IL-12p40- and IL-12p40/IL-18-deficient DCs impaired Th1 and Th17 differentiation. [•] IL-12p40 is more crucial than IL-18 in inducing Th1 and Th17 differentiation. [ABSTRACT FROM AUTHOR]

Abstract: Erythroid differentiation regulator 1 (Erdr1) suppressed cell motility in vitro and has anti-metastatic effect in vivo on melanoma. The current study investigated the effect of recombinant Erdr1 on the migration and invasion ability of SNU-216 cell, a gastric cancer cell line. The expression of Erdr1 is inversely correlated with IL-18 expression, which has a pro-cancer effect in gastric cancer. Treatment with rErdr1 markedly suppressed the ability of SNU-216 cells to migrate and invade, indicating that recombinant Erdr1 inhibited the motility of gastric cancer cells. E-cadherin expression levels were measured to determine the factor involved in the rErdr1-suppressed motility. E-cadherin is a representative of the cadherin family, known as cell motility enhancement adhesion molecule. Our results revealed that E-cadherin levels were increased by rErdr1 treatment, suggesting the involvement of E-cadherin in rErdr1-reduced cell migration. The cells were treated with specific MAPK inhibitors such as SP600125, SB203580 or PD98059 to identify the signaling mechanism involved with rErdr1 suppressed cell migration. The results indicated that the rErdr1 inhibited migration was primarily reversed by SP600125, a JNK inhibitor. In addition, the level of JNK phosphorylation was markedly increased by recombinant Erdr1. Taken together, these findings suggest that rErdr1 suppressed the ability of gastric cancer cells to metastasis by up regulating E-cadherin through a JNK pathway activation. Furthermore, it can be suggested that the inhibitory effect of recombinant Erdr1 on SNU-216 cell''s metastatic potential was through cell motility suppression. [Copyright &y& Elsevier]